Methods of inhibiting ovarian dysgenesis, delayed puberty, or sexual infantilism

ABSTRACT

A method of inhibiting ovarian dysgenesis, delayed puberty, or sexual infantilism comprising administering to a human in need thereof an effective amount of a compound having the formula ##STR1## wherein R 1  and R 3  are independently hydrogen, --CH 3 , ##STR2##  wherein Ar is optionally substituted phenyl; R 2  is selected from the group consisting of pyrrolidine, hexamethyleneamino, and piperidino; or a pharmaceutically acceptable salt of solvate thereof.

This application is a division of application Ser. No. 08/170,946 filedDec. 21, 1993, now U.S. Pat. No. 5,451,589.

BACKGROUND OF THE INVENTION

Delayed puberty is defined as a lack of physical manifestations ofsexual maturation in girls at a chronological age that is two standarddeviations above the mean age at the onset of puberty. This can befurther subdivided into several classification based on disorders thataffect operation of the luteinizing hormone-releasing hormone (LHRH)pulse generator, the pituitary gland, or the ovary. This includesidiopathic (constitutional) delay in growth and puberty,hypogonadotropic hypogonadism, and hypergonadotropic hypogonadism.

Idiopathic delay in growth generally applies to those girls whospontaneously enter puberty after the normal age of twelve. In mostcases, the first signs of secondary sexual development occurs within oneyear after treatment with LHRH or within one year after gonadotropin andestradiol concentrations begin to increase spontaneously. Thus, thechild usually reaches her full genetic potential in height and attainsfull sexual maturity, but it takes longer than usual. Growth velocity insubjects with constitutional delay in growth and adolescence returns tonormal after the onset of puberty. Treatment of delayed puberty dependson the the nature and severity of the disorder. Often treatment ofdelayed puberty for girls consists of a three month course of estrogenreplacement to initiate maturation of the secondary sexualcharacteristics.

Insufficient pulsatile secretion of LHRH and the resultingfollicle-stimulating hormone (FSH) and LH deficiency also leads tosexual infantilism. The LHRH deficiency may be secondary to a genetic ordevelopmental defect, or may be due to a tumor, inflammatory response,vascular lesion, or trauma. There are a variety of causes and disordersassociated with the disease. Gonadotropin deficiency may requiretreatment with estrogen replacement therapy at an age approximating thenormal age of puberty onset and continued until fertility is reached.

Primary ovarian failure and the impaired secretion of estrogen leads toa decreased negative feedback and elevated LH and FSH levels termedhypergonadotropic hypogonadism. This commonly is exhibited as Turner'sSyndrome and is treated with hormone replacement of estradiol beginningat age tweleve or thirteen to allow secondary sexual development at theappropriate chronological age.

Ovarian dysgenesis can be caused by many factors. Failure of ovariandevelopment or ovarian dysgenesis is commonly associated withhypopituitarism in childhood. Deficiency of the thyroid and adrenalcortex is currently corrected with replacement therapy, and the failureof sexual development is treated with estrogen.

Treatment at the normal age of puberty with hormone replacement can beexpected to have drawbacks. In addition, estrogens at high dosesaccelerate epiphyseal bone closure in tall girls, but is rarely usedbecause of the side-effects associated with such high dose regimens.Therefore there exists a need to find new methods for treating and/orpreventing the above.

SUMMARY OF THE INVENTION

This invention provides methods for inhibiting ovarian dysgenesis,delayed puberty, or sexual infantilism comprising administering to ahuman in need thereof an effective amount of a compound of formula I##STR3## wherein R¹ and R³ are independently hydrogen, --CH₃, ##STR4##wherein Ar is optionally substituted phenyl; R² is selected from thegroup consisting of pyrrolidino, hexamethyleneimino, and piperidino; andpharmaceutically acceptable salts and solvates thereof.

DETAILED DESCRIPTION OF THE INVENTION

The current invention concerns the discovery that a select group of2-phenyl-3-aroylbenzothiophenes (benzothiophenes), those of formula I,are useful for inhibiting ovarian dysgenesis, delayed puberty, or sexualinfantilism. The methods of use provided by this invention are practicedby administering to a human in need thereof a dose of a compound offormula I or a pharmaceutically acceptable salt or solvate thereof, thatis effective to inhibit ovarian dysgenesis, delayed puberty, or sexualinfantilism, or their attending symptoms. The term inhibit is defined toinclude its generally accepted meaning which includes prophylacticaladministration to a human subject to incurring on of the problemsdescribed or its symptoms, and holding in check and/or treating one ofthe problems described or its symptoms. As such, the present methodincludes both medical therapeutic and/or prophylactic treatment, asappropriate.

Raloxifene, a compound of this invention wherein it is the hydrochloridesalt of a compound of formula 1, R¹ and R³ are hydrogen and R² is1-piperidinyl, is a nuclear regulatory molecule. Raloxifene has beenshown to bind to the estrogen receptor and was originally thought to bea molecule whose function and pharmacology was that of an anti-estrogenin that it blocked the ability of estrogen to activate uterine tissueand estrogen dependent breast cancers. Indeed, raloxifene does block theaction of estrogen in some cells; however in other cell types,raloxifene activates the same genes as estrogen does and displays thesame pharmacology, e.g., osteoporosis, hyperlipidemia. As a result,raloxifene has been referred to as an anti-estrogen with mixedagonist-antagonist properties. The unique profile which raloxifenedisplays and differs from that of estrogen is now thought to be due tothe unique activation and/or suppression of various gene functions bythe raloxifene-estrogen receptor complex as opposed to the activationand/or suppression of genes by the estrogen-estrogen receptor complex.Therefore, although raloxifene and estrogen utilize and compete for thesame receptor, the pharmacological outcome from gene regulation of thetwo is not easily predicted and is unique to each.

Generally, the compound is formulated with common excipients, diluentsor carriers, and compressed into tablets, or formulated as elixirs orsolutions for convenient oral administration, or administered by theintramuscular or intravenous routes. The compounds can be administeredtransdermally, and may be formulated as sustained release dosage formsand the like.

The compounds used in the methods of the current invention can be madeaccording to established procedures, such as those detailed in U.S. Pat.Nos. 4,133,814, 4,418,068, and 4,380,635 all of which are incorporatedby reference herein. In general, the process starts with a benzob!thiophene having a 6-hydroxyl group and a 2-(4-hydroxyphenyl) group.The starting compound is protected, acylated, and deprotected to formthe formula I compounds. Examples of the preparation of such compoundsare provided in the U.S. patents discussed above. Optionally substitutedphenyl includes phenyl and phenyl substituted once or twice with C₁ -C₆alkyl, C₁ -C₄ alkoxy, hydroxy, nitro, chloro, fluoro, or tri(chloro orfluoro)methyl.

The compounds used in the methods of this invention formpharmaceutically acceptable acid and base addition salts with a widevariety of organic and inorganic acids and bases and include thephysiologically acceptable salts which are often used in pharmaceuticalchemistry. Such salts are also part of this invention. Typical inorganicacids used to form such salts include hydrochloric, hydrobromic,hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and the like.Salts derived from organic acids, such as aliphatic mono anddicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoicand hydroxyalkandioic acids, aromatic acids, aliphatic and aromaticsulfonic acids, may also be used. Such pharmaceutically acceptable saltsthus include acetate, phenylacetate, trifluoroacetate, acrylate,ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate,methoxybenzoate, methylbenzoate, o-acetoxybenzoate,naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate,β-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caprate,caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate,heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate,malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate,oxalate, phthalate, teraphthalate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate,propionate, phenylpropionate, salicylate, sebacate, succinate, suberate,sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate,benzene-sulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate,ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate,xylenesulfonate, tartarate, and the like. A preferred salt is thehydrochloride salt.

The pharmaceutically acceptable acid addition salts are typically formedby reacting a compound of formula I with an equimolar or excess amountof acid. The reactants are generally combined in a mutual solvent suchas diethyl ether or benzene. The salt normally precipitates out ofsolution within about one hour to 10 days and can be isolated byfiltration or the solvent can be stripped off by conventional means.

Bases commonly used for formation of salts include ammonium hydroxideand alkali and alkaline earth metal hydroxides, carbonates, as well asaliphatic and primary, secondary and tertiary amines, aliphaticdiamines. Bases especially useful in the preparation of addition saltsinclude ammonium hydroxide, potassium carbonate, methylamine,diethylamine, ethylene diamine and cyclohexylamine.

The pharmaceutically acceptable salts generally have enhanced solubilitycharacteristics compared to the compound from which they are derived,and thus are often more amenable to formulation as liquids or emulsions.

Pharmaceutical formulations can be prepared by procedures known in theart. For example, the compounds can be formulated with commonexcipients, diluents, or carriers, and formed into tablets, capsules,suspensions, powders, and the like. Examples of excipients, diluents,and carriers that are suitable for such formulations include thefollowing: fillers and extenders such as starch, sugars, mannitol, andsilicic derivatives; binding agents such as carboxymethyl cellulose andother cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone; moisturizing agents such as glycerol; disintegrating agentssuch as calcium carbonate and sodium bicarbonate; agents for retardingdissolution such as paraffin; resorption accelerators such as quaternaryammonium compounds; surface active agents such as cetyl alcohol,glycerol monostearate; adsorptive carriers such as kaolin and bentonite;and lubricants such as talc, calcium and magnesium stearate, and solidpolyethyl glycols.

The compounds can also be formulated as elixirs or solutions forconvenient oral administration or as solutions appropriate forparenteral administration, for instance by intramuscular, subcutaneousor intravenous routes. Additionally, the compounds are well suited toformulation as sustained release dosage forms and the like. Theformulations can be so constituted that they release the activeingredient only or preferably in a particular part of the intestinaltract, possibly over a period of time. The coatings, envelopes, andprotective matrices may be made, for example, from polymeric substancesor waxes.

The particular dosage of a compound of formula I required to inhibitovarian dysgenesis, delayed puberty, or sexual infantilism, or attendingsymptoms, according to this invention will depend upon the severity ofthe condition, the route of administration, and related factors thatwill be decided by the attending physician. Generally, accepted andeffective daily doses will be from about 0.1 to about 1000 mg/day, andmore typically from about 50 to about 200 mg/day. Such dosages will beadministered to a subject in need thereof from once to about three timeseach day, or more often as needed to effectively treat ovariandysgenesis, delayed puberty, or sexual infantilism, or symptoms thereof.Also, other active ingredients may be administered to a human in need,such as LHRH agonists or progestins.

It is usually preferred to administer a compound of formula I in theform of an acid addition salt, as is customary in the administration ofpharmaceuticals bearing a basic group, such as the piperidino ring. Itis also advantageous to administer such a compound by the oral route.For such purposes the following oral dosage forms are available.

FORMULATIONS

In the formulations which follow, "active ingredient" means a compoundof formula I.

Formulation 1: Gelatin Capsules

Hard gelatin capsules are prepared using the following:

    ______________________________________                                        Ingredient        Quantity (mg/capsule)                                       ______________________________________                                        Active ingredient 0.1-1000                                                    Starch, NF        0-650                                                       Starch flowable powder                                                                          0-650                                                       Silicone fluid 350 centistokes                                                                  0-15                                                        ______________________________________                                    

The ingredients are blended, passed through a No. 45 mesh U.S. sieve,and filled into hard gelatin capsules.

Examples of specific capsule formulations of raloxifene, that have beenmade include those shown below:

Formulation 2: Raloxifene capsule

    ______________________________________                                        Ingredient        Quantity (mg/capsule)                                       ______________________________________                                        Raloxifene        1                                                           Starch, NF        112                                                         Starch flowable powder                                                                          225.3                                                       Silicone fluid 350 centistokes                                                                  1.7                                                         ______________________________________                                    

Formulation 3: Raloxifene capsule

    ______________________________________                                        Ingredient        Quantity (mg/capsule)                                       ______________________________________                                        Raloxifene        5                                                           Starch, NF        108                                                         Starch flowable powder                                                                          225.3                                                       Silicone fluid 350 centistokes                                                                  1.7                                                         ______________________________________                                    

Formulation 4: Raloxifene capsule

    ______________________________________                                        Ingredient        Quantity (mg/capsule)                                       ______________________________________                                        Raloxifene        10                                                          Starch, NF        103                                                         Starch flowable powder                                                                          225.3                                                       Silicone fluid 350 centistokes                                                                  1.7                                                         ______________________________________                                    

Formulation 5: Raloxifene capsule

    ______________________________________                                        Ingredient        Quantity (mg/capsule)                                       ______________________________________                                        Raloxifene        50                                                          Starch, NF        150                                                         Starch flowable powder                                                                          397                                                         Silicone fluid 350 centistokes                                                                  3.0                                                         ______________________________________                                    

The specific formulations above may be changed in compliance with thereasonable variations provided.

A tablet formulation is prepared using the ingredients below:

Formulation 6: Tablets

    ______________________________________                                        Ingredient       Quantity (mg/tablet)                                         ______________________________________                                        Active ingredient                                                                              0.1-1000                                                     Cellulose, microcrystalline                                                                    0-650                                                        Silicon dioxide, fumed                                                                         0-650                                                        Stearate acid    0-15                                                         ______________________________________                                    

The components are blended and compressed to form tablets.

Alternatively, tablets each containing 0.1-1000 mg of active ingredientare made up as follows:

Formulation 7: Tablets

    ______________________________________                                        Ingredient         Quantity (mg/tablet)                                       ______________________________________                                        Active ingredient  0.1-1000                                                   Starch             45                                                         Cellulose, microcrystalline                                                                      35                                                         Polyvinylpyrrolidone                                                                             4                                                          (as 10% solution in water)                                                    Sodium carboxymethyl cellulose                                                                   4.5                                                        Magnesium stearate 0.5                                                        Talc               1                                                          ______________________________________                                    

The active ingredient, starch, and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50°-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate, and talc, previouslypassed through a No. 60 U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yieldtablets.

Suspensions each containing 0.1-1000 mg of medicament per 5 mL dose aremade as follows:

Formulation 8: Suspensions

    ______________________________________                                        Ingredient          Quantity (mg/5 ml)                                        ______________________________________                                        Active ingredient   0.1-1000    mg                                            Sodium carboxymethyl cellulose                                                                    50          mg                                            Syrup               1.25        mg                                            Benzoic acid solution                                                                             0.10        mL                                            Flavor              q.v.                                                      Color               q.v.                                                      Purified water to   5           mL                                            ______________________________________                                    

The medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethyl cellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor, and color are diluted with some of thewater and added, with stirring. Sufficient water is then added toproduce the required volume.

TEST PROCEDURE

Five to fifty females are selected for the clinical study. The femalesare between the ages of twelve and eighteen and have been diagnosed withovarian dysgenesis, delayed puberty, or sexual infantilism, but are ingood general health otherwise. The study has a placebo control group,i.e., the females are divided into two groups, one of which receives theactive agent of this invention and the other receives a placebo. Femalesin the test group receive between 50-200 mg of the active agent per dayby the oral route. They continue this therapy for 2-12 months. Accuraterecords are kept as to the status of the problem and symptoms thereof inboth groups and at the end of the study these results are compared. Theresults are compared both between members of each group and also theresults for each patient are compared to the status reported on eachpatient before the study began.

Utility of the compounds of the invention is illustrated by the positiveimpact they have on ovarian dysgenesis, delayed puberty, or sexualinfantilism and/or one or more of attending symptoms when used in astudy as above.

I claim:
 1. A method of inhibiting ovarian dysgenesis, delayed puberty,or sexual infantilism comprising prophyactically administering to ahuman in need thereof an effective amount of a compound having theformula ##STR5## wherein R¹ and R³ are independently hydrogen, --CH₃,##STR6## wherein Ar is optionally substituted phenyl; R² is selectedfrom the group consisting of pyrrolidine, hexamethyleneamino, andpiperidino; or a pharmaceutically acceptable salt of solvate thereof. 2.The method of claim 1 wherein said compound is the hydrochloride saltthereof.
 3. The method of claim 1 wherein said compound is ##STR7## orits hydrochloride salt.
 4. The method of claim 1 wherein said human isunder the age of eighteen.
 5. The method of claim 1 wherein said humanis also administered a progestin.